Project Summary/Abstract Cholera, a severe waterborne infection caused by virulent strains of the bacterium Vibrio cholerae, remains a significant public heath burden in the developing world. In recent years, it has expanded in Africa and South Asia and re-emerged in the Americas, with an estimated 2 -- 4 million of cases per year reported by the World Health Organization (WHO). Effective outbreak response and control strategies for cholera rely on an analysis of the epidemiologic triad of pathogen, host, and environment and a deep understanding of their underlying dynamics. There is currently a paucity of research examining such dynamics. Particularly, the bacterial dynamics associated with the pathogen Vibrio cholerae are a critical, yet not well understood, factor that shapes the complex epidemics and endemics of cholera. The overall objective of this proposal is to establish a new mathematical and computational cholera modeling framework, guided by biological experiments, to investigate the pathogen dynamics in the environment and within the human body. To achieve this objective, we will pursue three specific aims: (1) Modeling the environmental bacterial dynamics; (2) Modeling the within-host bacterial dynamics; and (3) Linking and computing the between- host/within-host dynamics. The proposed research is significant because it is expected to vertically advance our current understanding of cholera dynamics, particularly the bacterial evolution in the environment and within the human body, which spans vastly different time scales and which is important for the control and management of cholera. The approach is innovative in the development of a sophisticated, multi-scale mathematical framework that incorporates detailed dynamics of the pathogen evolution in the environment and pathogen-host interaction within the human body, and in the integration of rigorous mathematical modeling and analysis, intensive and advanced computation, carefully designed biological experiments, and realistic epidemic data. The project represents an interdisciplinary collaboration among an applied and computational mathematician with long-term interest in cholera modeling, a microbiologist, and a bioengineer. The success of this project will not only build a solid knowledge base for the complex dynamics of cholera, but also provide important guidelines for the public health administrations in disease management and policy development.